During the previous funding period we made several key observations in a follow-up study of a healthy elderly cohort. 1) The prevalence and incidence of Alzheimer's disease (AD) and dementia associated with stroke (DAS, defined broadly as dementia in individuals with evidence of cerebrovascular disease) were significantly higher among African-Americans and Hispanics than Caucasians. 2) The cumulative incidence of AD to age 90 was significantly higher without, than with, and APOE-epsilon4 allele among African-Americans and Hispanics compared to Caucasians. 3) AD risk was significantly lower among postmenopausal women who used estrogen compared to women who did not, regardless of their age, APOE genotype, education or ethnic background. 4) The risk of DAS is higher among individuals with an APOE-epsilon4 allele and preliminary evidence suggests that increased levels of low density lipoprotein (LDL) and an increased ratio of total cholesterol to high density lipoprotein (HDL)-cholesterol imposes a higher risk of DAS. These observations and others described in preliminary work provide a unique opportunity to understand mechanisms related to the disease risk and risk reduction. We shall expand our epidemiologic inquiry in this multi-ethnic community by refreshing the follow-up cohort and enhancing the laboratory component. We will study the cumulative risk of AD across ethnic groups by analysis of APOE flanking region haplotypes to identify polymorphisms in enhancer/promoter regions of APOE. We will study the cumulative risk of DAS in relation to lipids and lipoproteins and APOE genotype and investigate the stroke subtype sin DAS. We will study the cumulative risk of AD by amyloid beta proteins 1-42 and 1-20 in plasma and investigate changing levels of these proteins with disease progression. We will study the cumulative risk of AD and DAS by systemic levels of gonadal and adrenal steroids and continue our investigation of protective factors such as non-steroidal anti-inflammatory drugs, alcohol and increased physical activity as well as other risk factors such as smoking. The new cohort will allow us to exploit the findings in our previous funding period and develop a significantly enhanced laboratory investigation of genes and biological indicators of risk and risk and risk modification of AD and DAS.